The present invention relates to the novel quinolone carboxylic acid derivatives, their esters, their pharmaceutically acceptable salts and their hydrates as shown in formula (I) and a process for preparing these compounds. Furthermore, some of the invented quinolone carboxylic acid derivatives as shown in formula (I) show broad spectrum and excellent pharmacokinetic properties and low toxicity. ##STR5## wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,
Y is a hydrogen or methyl group, PA1 R.sup.1 is a hydrogen or C.sub.1 -C.sub.5 alkyl group, PA1 R.sup.2 is ##STR6## (wherein A and B are fluorocarbon or nitrogen atom, provided that if A.dbd.CF, B.dbd.N and if A.dbd.N, B.dbd.CF) PA1 R.sup.3 is ##STR7## (wherein R.sup.4 is an amino group to make a racemate or (S)-enantiomer.) or ##STR8## (wherein R.sup.5, R.sup.6 and R.sup.7 are H-- or C.sub.1 -C.sub.3 alkyl groups.) PA1 Y is a hydrogen or methyl group, PA1 R.sup.1 is a hydrogen or C.sub.1 -C.sub.5 group, PA1 R.sup.2 is ##STR10## wherein A and B are fluorocarbon or nitrogen atom, provided that if A.dbd.CF, B.dbd.N and if A.dbd.N, B.dbd.CF) PA1 R.sup.3 is ##STR11## (wherein R.sup.4 is an amino group to make a racemate or (S)-enantiomer.) or PA1 R.sup.3 is ##STR12## (wherein R.sup.5, R.sup.6 and R.sup.7 are H-- or C.sub.1 -C.sub.3 alkyl groups.) PA1 1. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoli ne-3-carboxylic acid PA1 2. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-o xoquinoline-3-carboxylic acid PA1 3. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-o xoquinoline-3-carboxylic acid PA1 4. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro -4-oxoquinoline-3-carboxylic acid PA1 5. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-o xoquinoline-3-carboxylic acid PA1 6. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydr o-4-oxoquinoline-3-carboxylic acid PA1 7. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-na phthyridine-3-carboxylic acid PA1 8. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-n aphthyridine-3-carboxylic acid 9. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-o xo-1,8-naphthyridine-3-carboxylic acid PA1 10. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro -4-oxo-1,8-naphthyridine-3-carboxylic acid PA1 11. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydr o-4-oxo-1,8-naphthyridine-3-carboxylic acid PA1 12. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-na phthyridine-3-carboxylic acid PA1 13. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-o xo-1,8-naphthyridine-3-carboxylic acid PA1 14. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-o xo-1,8-naphthyridine-3-carboxylic acid PA1 15. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro -4-oxo-1,8-naphthyridine-3-carboxylic acid PA1 16. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-o xo-1,8-naphthyridine-3-carboxylic acid PA1 17. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoli ne-3-carboxylic acid PA1 18. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid PA1 19. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-o xoquinoline-3-carboxylic acid PA1 20. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro -4-oxoquinoline-3-carboxylic acid PA1 21. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-o xoquinoline-3-carboxylic acid PA1 22. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydr o-4-oxoquinoline-3-carboxylic acid PA1 23. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoqui noline-3-carboxylic acid PA1 24. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro -4-oxoquinoline-3-carboxylic acid PA1 25. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro -4-oxoquinoline-3-carboxylic acid PA1 26. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dih ydro-4-oxoquinoline-3-carboxylic acid PA1 27. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro -4-oxoquinoline-3-carboxylic acid PA1 28. 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-di hydro-4-oxoquinoline-3-carboxylic acid PA1 29. 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-di hydro-4-oxoquinoline-3-carboxylic acid
In general, most of the quinolone-type antibiotics which have been heretofore developed are ones having small alkyl and cycloalkyl group at N-1 position [e.g. Norfloxacin: U.S. Pat. No. 4,146,719, Ciprofloxacin: [U.S. Pat. No. 4,620,007] and ones having aromatic group at N-1 position [e.g. Temafloxacin: J. Med. Chem., 34, 168 (1991), Tosufloxacin: U.S. Pat. No. 4,704,459].
However, a noticeable quinolone antibiotic having heteroaromatic group at N-1 position has not been yet developed. Otsuka, Toyama and others reported their researches upon introducing heteroaromatic group such as furyl, thienyl, thiazol, imidazol, pyridyl, pyrimidyl group at N-I position, but a compound available in vivo has not been yet developed. (JPK 61-251667-A, 62-174053-A, 02-85255-A).
In particular, the compounds developed up to now generally have good in vitro activity, but such in vitro activity could not leads to in vivo because of poor pharmacokinetics including half-life (t.sub.1/2), maximum blood level (C.sub.max), bioavilability (BA), area under curve (AUC) etc, which are important properties of a compound for good in vitro activity to be maintained in vivo.
Therefore, the object of this invention is to develope compounds having excellent pharmacokinetic properties by introducing fluoro pyridyl group which is a heteroaromatic group at N-1 position, thereby to produce compounds having good antibiotic power in vivo and long half-life (t.sub.1/2) which enable once a day of dose. Therefore, the present invention provides a series of compounds having even more excellent pharmacokinetic properties than those of the conventional quinolone antibiotics by introducing 5-fluoro-2-pyridyl group and 3-fluoro-4-pyridyl group into mother nuclei of quinolone and naphthyridine.